1

DRUG DISCOVERY

• Random Searche.g., buying paintbrush, mop, hammer, gluestick, nail, etc. etc.for hanging a picture frame on the wall

• Rational Designe.g., buying a nail for hanging the frame

• Combinatorial Searche.g., buying a box of nails of different sizes for hanging the frame

2

~ 5 IND

~ 250 in vivo

~ 500 in vitro

> 10,000 compounds

> 15 years ~ 1 NDA > $500 million

Time Cost

WHY COMBINATORIAL CHEMISTRY?

3

Biological Discovery

High VolumeScreening

CombinatorialDiversity

Structure, Design, Informatics

Lead Series

Biodisposition

Toxicity

Efficacy

Pharmacokinetics

INDIND

Lead Discovery Iterative PreclinicalResearch Process R&D

FULL TOOLBOX REQUIRED TO COMPETE

4

GENERATING A COMBINATORIAL LIBRARY

X X X Y Y Y+

……….. 9 products

MIXTURE SYNTHESIS

5Ser Ala Tyr Arg

SPATIALLY ADDRESSABLE SYNTHESIS

X Y+I)

X Y+II)

X Y+III)

6

SPLIT AND MIX STRATEGY

X X X

Y

Y YY

MIX

SPLIT

7

SPLIT AND MIX STRATEGY

MIX and SPLIT

8

DECONVOLUTION BY TAGGING

Y

Y YY

X X X

MIX

SPLIT

9

DECONVOLUTION BY TAGGING (continued)

MIX and SPLIT

10

DECONVOLUTION BY ENCODED DNA

MIX and SPLIT

SPLIT

A1

N1

A2

N2

A3

N3

A2A2A1A2

N1N2 N2N2

A3A2

N3N2

A2A1A1A1

N1N1 N2N1

A3A1

N3N1

A2A3A1A3

N1N3 N2N3

A3A3

N3N3

A2 A3 A1